This is a one-year R01 application in response to RFA-DK-12-025 entitled Urologic Chronic Pelvic Pain Syndrome (UCPPS) Research (R01). There are no effective treatments for UCPPS. Recent preliminary results from the Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network indicate global and local brain anatomical and functional abnormalities in men with UCPPS. Thus, renormalization of the urological pain-related brain reorganization is a viable and objective target for treating UCPPS. Our recent human studies in other chronic pain conditions indicate that placebo alone may be an efficient treatment in some patients. Also, our animal studies show that D-cycloserine (DCS, targeting the frontal cortex) can reverse many of the signs of neuropathic pain in rodents. These results indicate that urological pain relief by placebo and by DCS are potential therapy options for UCPPS, each of which may be mediated through distinct brain circuitry. Here we test the efficacy of DCS and placebo, in comparison to each other and to no-treatment, in a double blind, three-armed, brain imaging-based randomized clinical trial in men with UCPPS. Brain anatomy and function are monitored repeatedly, and urological pain is measured with questionnaires and using a smart phone App (to collect pain ratings in the natural setting of everyday life, 3 times a day). Participants undergo a 2-week observation period, a 3-month treatment period, a 2-week washout period, and a final period wherein participants choose to continue on one of the two treatments for another month. The trial will permit us to address three specific aims: Aim 1: Evaluate differential efficacy for UCPPS urological pain relief between placebo and DCS. Aim 2: Evaluate differential brain functional biomarkers for treatment response and treatment propensity, for placebo and for DCS. Aim 3: Demonstrate that brain morphology renormalizes in treatment responders. Given the financial and time constraints of this RFA, the study is powered to be a proof of concept and to demonstrate the strength of the methodology in providing objective evidence for individualized treatment choices when evaluating novel therapies in UCPPS.